The disorder acute necrotizing encephalopathy (ANE) affects children. It manifests as hemorrhagic, necrotic lesions in the thalamus and brainstem occurring within days after the onset of a febrile illness. These lesions may resolve, or lead to permanent disability or death. The disorder appears to be distributed worldwide. ANE has been regarded a para-infectious disorder and previous studies have investigated viral action or systemic cytokine responses, but no causative mechanism has been identified. I propose that new insights about ANE may come from families in which ANE appears to segregate as a Mendelian disease. We have identified one family in which ANE segregates as an autosomal dominant disorder with incomplete penetrance; we have found two other families in which ANE also clusters. Using the original family, we have mapped their disease to a small interval on human chromosome 2q. In addition, we have performed biochemical studies of oxidative phosphorylation in isolated muscle mitochondria from one family member and have detected a loose coupling. I intend to identify the genetic and biochemical contributions to ANE by pursuing two independent and complementary approaches. The first will identify causative genes through linkage analysis and candidate gene sequencing in affected families. The second will examine patient derived cell cultures for defects in oxidative phosphorylation. The synergistic approach that these Aims employ will result in a much stronger characterization of the pathogenic mechanisms that cause ANE. This proposal will serve the candidate's long term goal of becoming an independent investigator in the field of genetics, with special focus on mitochondrial function and neurodegeneration. My co-mentors Drs. Warman and Hoppel provide the requisite expertise to enable me to find the causative gene and characterize its function. The Case Western Reserve University Department of Genetics and the Center for Inherited Disorders of Energy Metabolism will provide the ideal training environment.